Počet záznamů: 1  

Nonhydrolysable Analogues of (p)ppGpp and (p)ppApp Alarmone Nucleotides as Novel Molecular Tools

  1. 1.
    SYSNO ASEP0545506
    Druh ASEPJ - Článek v odborném periodiku
    Zařazení RIVJ - Článek v odborném periodiku
    Poddruh JČlánek ve WOS
    NázevNonhydrolysable Analogues of (p)ppGpp and (p)ppApp Alarmone Nucleotides as Novel Molecular Tools
    Tvůrce(i) Mojr, Viktor (UOCHB-X) ORCID
    Roghanian, M. (SE)
    Tamman, H. (BE)
    Do Pham, Duy Dinh (UOCHB-X) ORCID
    Petrová, Magdalena (UOCHB-X) RID
    Pohl, Radek (UOCHB-X) RID, ORCID
    Takada, H. (JP)
    Van Nerom, K. (BE)
    Ainelo, H. (BE)
    Caballero-Montes, J. (BE)
    Jimmy, S. (SE)
    Garcia-Pino, A. (BE)
    Hauryliuk, V. (EE)
    Rejman, Dominik (UOCHB-X) RID, ORCID
    Zdroj.dok.ACS Chemical Biology. - : American Chemical Society - ISSN 1554-8929
    Roč. 16, č. 9 (2021), s. 1680-1691
    Poč.str.12 s.
    Jazyk dok.eng - angličtina
    Země vyd.US - Spojené státy americké
    Klíč. slovapppGpp ; pppApp ; nonhydrolysable ; molecular tools
    Obor OECDOrganic chemistry
    CEP8F19006 GA MŠMT - Ministerstvo školství, mládeže a tělovýchovy
    Způsob publikováníOmezený přístup
    Institucionální podporaUOCHB-X - RVO:61388963
    UT WOS000697343400008
    DOI10.1021/acschembio.1c00398
    AnotaceWhile alarmone nucleotides guanosine-3′,5′-bisdiphosphate (ppGpp) and guanosine-5′-triphosphate-3′-diphosphate (pppGpp) are archetypical bacterial second messengers, their adenosine analogues ppApp (adenosine-3′,5′-bisdiphosphate) and pppApp (adenosine-5′-triphosphate-3′-diphosphate) are toxic effectors that abrogate bacterial growth. The alarmones are both synthesized and degraded by the members of the RelA-SpoT Homologue (RSH) enzyme family. Because of the chemical and enzymatic liability of (p)ppGpp and (p)ppApp, these alarmones are prone to degradation during structural biology experiments. To overcome this limitation, we have established an efficient and straightforward procedure for synthesizing nonhydrolysable (p)ppNuNpp analogues starting from 3′-azido-3′-deoxyribonucleotides as key intermediates. To demonstrate the utility of (p)ppGNpp as a molecular tool, we show that (i) as an HD substrate mimic, ppGNpp competes with ppGpp to inhibit the enzymatic activity of human MESH1 Small Alarmone Hyrolase, SAH, and (ii) mimicking the allosteric effects of (p)ppGpp, (p)ppGNpp acts as a positive regulator of the synthetase activity of long ribosome-associated RSHs Rel and RelA. Finally, by solving the structure of the N-terminal domain region (NTD) of T. thermophilus Rel complexed with pppGNpp, we show that as an HD substrate mimic, the analogue serves as a bona fide orthosteric regulator that promotes the same intra-NTD structural rearrangements as the native substrate.
    PracovištěÚstav organické chemie a biochemie
    Kontaktasep@uochb.cas.cz ; Kateřina Šperková, Tel.: 232 002 584 ; Jana Procházková, Tel.: 220 183 418
    Rok sběru2022
    Elektronická adresahttps://doi.org/10.1021/acschembio.1c00398
Počet záznamů: 1  

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